The present invention relates to labeled compounds and more particularly to compounds labeled with carbon-13 and hydrogen-2.
Stable isotope labeled amino acids and nucleotides are required for structural and mechanistic studies of proteins and oligonucleotides. In addition, isotopically labeled biologically active compounds are required for many phases of drug discovery and development including elucidation of biosynthetic pathways, pharmacokinetics, and drug metabolism. For many applications, site-specific 13C or combined 13C and 2H labeling are required. While a number of stable isotope labeled compounds are available from companies such as Sigma-Aldrich Chemicals, a need remains for other labeled synthetic precursors.
Methyl aryl sulfones such as methyl phenyl sulfone and methyl aryl sulfoxides such as methyl phenyl sulfoxide have been used in a wide number of reactions to make a large number of such biomolecules and other important synthetic precursors. For example, methyl phenyl sulfone can be used as a nucleophilic synthon and is easily converted into an electrophilic synthon. While methyl phenyl sulfone and methyl phenyl sulfoxide could provide a chemically stable and non-volatile carrier for the valuable 13C and 2H labels, the preparation of few isotopically labeled methyl phenyl sulfones and methyl phenyl sulfoxides has been previously accomplished. One example of isotopically labeled methyl phenyl sulfoxide and methyl phenyl sulfone are shown by Chaudhary et al., J. Labelled Cpd. Radiopharm., 43, 683-691 (2000), although they were not described or suggested as synthetic reagents for synthesis of labeled compounds. Availability of other significant [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl phenyl sulfones and [2H1, 13C], [2H2, 13C] and [2 H3, 13C]methyl phenyl sulfoxides would allow researchers to take advantage of the wealth of chemistry that has been done using unlabeled methyl phenyl sulfone and methyl phenyl sulfoxide.
As carbon-13 is separated from its lighter isotope by cryogenic distillation of carbon monoxide (CO), all labeled carbons are derived ultimately from CO. The highly efficient conversion of CO to useful chemical precursors is perhaps the most unique aspect of stable isotope labeling technology. Any inefficiencies in the early synthetic steps add greatly to the overall expense of isotope labeling. Thus, considerable efforts have been directed to the development of methods for the preparation of useful synthetic precursors or synthons. This effort has given rise to efficient large-scale methods for the synthesis of methane, methanol, methyl iodide, sodium formate, potassium cyanide and carbon dioxide. These methods are the foundation of all labeling chemistry. The most useful of the electrophilic one-carbon precursors, methyl iodide and carbon dioxide, are difficult to store and use efficiently due to their high volatility.
As spectroscopic instrumentation and techniques continue to improve, there is a drive to study ever more complicated bio-systems. This has lead to demands for more complex labeling patterns in biomolecules. In the past, the simple introduction of a labeled atom site-specifically without stereospecificity was the major thrust for stable isotope labeling and the first generation of labeled synthons served this effort well. Increasingly, in today""s labeling climate, in addition to site-specific labeling, the requirement for stereospecificity has been added. This includes both the ability to stereospecific label chiral compounds as well as the ability to differentiate between prochiral centers with deuterium or carbon. The development of additional synthons as starting materials will address those growing demands.
Accordingly, it is an object of the present invention to provide labeled compounds.
In accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention provides labeled compounds, [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones wherein the 13C methyl group attached to the sulfur of the sulfone includes exactly one, two or three deuterium atoms and the aryl group is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure 
wherein R1, R2, R3, R4 and R5 are each independently, hydrogen, a C1-C4 lower alkyl, a halogen, an amino group from the group consisting of NH2, NHR and NRRxe2x80x2 where R and Rxe2x80x2 are each a C1-C4 lower alkyl, a phenyl, or an alkoxy group.
The present invention further provides a process of preparing methyl aryl sulfone by reacting a methyl aryl sulfide with an oxidizing agent of potassium peroxymonosulfate to form a methyl aryl sulfone.
The present invention still further provides labeled compounds, [2 H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfoxides wherein the 13C methyl group attached to the sulfur of the sulfoxide includes exactly one, two or three deuterium atoms and the aryl group is selected from the group consisting of 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure: 
wherein R1, R2, R3, R4 and R5 are each independently, hydrogen, a C1-C4 lower alkyl, a halogen, an amino group from the group consisting of NH2, NHR and NRRxe2x80x2 where R and Rxe2x80x2 are each a C1-C4 lower alkyl, a phenyl, or an alkoxy group.
The present invention further provides a process of preparing methyl aryl sulfoxide by reacting a methyl aryl sulfide with hydrogen peroxide to form a methyl aryl sulfoxide.
Methyl aryl sulfones and methyl aryl sulfoxides are useful organic reagents that allow for the preparation of many biochemicals and materials. Isotopically labeled methyl aryl sulfones and methyl aryl sulfoxides can be used to introduce a carbon-13 [13C] and a hydrogen-2 or deuterium label [2H] into such biochemicals and materials. As used herein, the term xe2x80x9carylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two, three, four or five substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, and xe2x80x94COOR (where R is hydrogen or alkyl). More specifically, the term xe2x80x9carylxe2x80x9d includes, but is not limited to 1-naphthyl, substituted 1-naphthyl, 2-naphthyl, substituted 2-naphthyl, and phenyl groups with the structure 
wherein R1, R2, R3, R4 and R5 are each independently a lower alkyl, i.e., a C1-C4 alkyl such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, and tert-butyl, a halogen such as chloro, bromo or iodo, an amino group such as NH2, NHR or NRRxe2x80x2 where R and Rxe2x80x2 are each a lower alkyl or aryl as described above, or an alkoxy group such as O-alkyl or O-aryl where the alkyl is a lower alkyl as described above or an aryl as described above.
As used herein, the term xe2x80x9c[2H1, 13C]xe2x80x9d means exactly one deuterium atom, the term xe2x80x9c[2H2, 13C]xe2x80x9d means exactly two deuterium atoms, and the term xe2x80x9c[2H3, 13C]xe2x80x9d means exactly three deuterium atoms within the respective compound.
[2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones can be made from [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfides in a one step process as shown below. Such a process can involve reaction of the sulfide with a mild oxidizing agent such as Oxone(copyright) (potassium peroxymonosulfate) at room temperature for from several hours up to several days. Other reaction temperatures may be used if desired. Such [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones can be used as a non-volatile carrier of the desired carbon and hydrogen labels. Methyl aryl sulfones without the isotopic substitution can be made in high yields by the same process.
13CD3S-arylxe2x86x9213CD3SO2-aryl Oxone(copyright)
[2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfoxides can also be made from [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfides in a one step process as shown below. Such a process can involve reaction of the sulfide with hydrogen peroxide at room temperature for several hours. Other reaction temperatures may be used if desired. Such [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfoxides can be used as a non-volatile carrier of the desired carbon and hydrogen labels. Methyl aryl sulfoxides without the isotopic substitution can be made in high yields by the same process.
13CD3S-arylxe2x86x9213CD3SO-aryl H2O2
Availability of the [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones having the structure: 
wherein R1, R2, R3, R4 and R5 are each independently a lower alkyl, i.e., a C1-C4 alkyl such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, and tert-butyl, a halogen such as chloro, bromo or iodo, an amino group such as NH2, NHR or NRRxe2x80x2 where R and Rxe2x80x2 are each a lower alkyl or aryl as described above, or an alkoxy group such as O-alkyl or O-aryl where the alkyl is a lower alkyl as described above or an aryl as described above, and the methyl group attached to the sulfide includes exactly one, two or three deuterium atoms and [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfoxides having the structure 
wherein R1, R2, R3, R4 and R5 are each independently a lower alkyl, i.e., a C1-C4 alkyl such as methyl, ethyl, n-propyl, iso-propyl, butyl, isobutyl, and tert-butyl, a halogen such as chloro, bromo or iodo, an amino group such as NH2, NHR or NRRxe2x80x2 where R and Rxe2x80x2 are each a lower alkyl or aryl as described above, or an alkoxy group such as O-alkyl or O-aryl where the alkyl is a lower alkyl as described above or an aryl as described above, and the 13C methyl group attached to the sulfur of the sulfide includes exactly one, two or three deuterium atoms will allow researchers to take advantage of the wealth of chemistry that has been done using unlabeled methyl aryl sulfones and unlabeled methyl aryl sulfoxides.
The present invention provides [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones, i.e., [13C]methyl aryl sulfone wherein the 13C methyl group attached to the sulfur group of the sulfone includes exactly one, two or three deuterium atoms. For those molecules with exactly one or two deuterium atoms, such isotopically differentiated methyl groups can be attractive for a variety of applications. For example, a chirally differentiated isopropyl group, i.e., xe2x80x94CH(13 CDH2)(13CD2H) can be produced.
Similarly, the present invention provides [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfoxides, i.e., [13C]methyl aryl sulfoxide wherein the 13C methyl group attached to the sulfur of the sulfoxide includes exactly one, two or three deuterium atoms. As noted before, for those molecules with exactly one or two deuterium atoms, such isotopically differentiated methyl groups can be attractive for a variety of applications.
The present invention provides efficient large scale one-pot processes for the preparation of methyl aryl sulfones, e.g., [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones from [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfides. Such processes can avoid the inevitable losses resulting from the isolation of labeled methyl iodide. Such methyl aryl sulfones can provide a chemically stable and non-volatile carrier for valuable 13C and 2H labels.
In addition, an efficient process for the preparation of methyl aryl sulfones, e.g., [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones, by oxidation of [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfides is provided. In the process of the present invention, [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones can be prepared in a high yield ( greater than 98%) process by oxidizing [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfides to produce [2H1, 13C], [2H2, 13C] and [2H3, 13C]methyl aryl sulfones.
The present invention is more particularly described in the following examples which are intended as illustrative only, since numerous modifications and variations will be apparent to those skilled in the art.